Release, drug formulation modified

Since nicotinic acid can cause unpleasant flushing and other symptoms of vasodilatation, attempts have been made to develop modified-release formulations. Modified-released nicotinic acid formulations may be better tolerated than the immediate-release formulation, because they reduce the vasodilatory effects of the drug. However, the low frequency of flushing produced by modified-release formulations may be offset by an increased risk of hepatotoxicity. Some reports have suggested a higher frequency of hepatic dysfunction with traditional modified-release nicotinic acid formulations compared with immediate-release products (2, 40). 

II.S.16 Special Situations for Drug Delivery Modified Release Formulations... 

One of the special situations for drug delivery is the assessment of the pharmacokinetic (PK) properties of a modified release formulation. Modified release products always gain importance if the PK/PD profile of a drug is not close to optimal for its target indication, mostly because the (short) PK or efficacy half-life does not match the intended dosing frequency. 

In a four-way crossover study in 16 healthy men a mod-ified-release formulation of metoclopramide (30 mg) administered fasting and after a high-fat meal, an immediate-release formulation (30 mg) and a short intravenous infusion of 30 mg have been compared (16). The absolute systemic availability of the modified-release formulation was about 17% lower than that of the immediate-release formulation. Food had no significant effect on absorption. Uniform absorption of the drug from modified-release formulations supports their use in long-term treatment. 

These enzymes (and transporters) exhibit differential expression at various sites throughout the GIT. For example, CYP3A4 expression is highest in the duodenum and lowest in the colon conversely, the expression of P-gp is greatest in the colon. This has implications for the gut wall first-pass extraction of drugs delivered by modified-release formulations, where the majority of the drug must be absorbed from the colon. 

The bacteria in the intestinal tract serve as another well-known source of luminal drug degradation [61], though this is only important for the colon region as the luminal concentration of bacteria is 104 to 109-fold higher in the colon compared with the small intestine. Thus, this aspect is only relevant for drugs that reach this region, for example, due to poor permeability, slow dissolution or delivery by modified-release formulations. Hydrolytic and other reductive reactions are predominantly mediated by bacterial enzymes, and a list of the most prominent types... 

Indiplon is rapidly absorbed (1-2 h) and eliminated (ti/2 =1.3 h). In-vitro studies on indiplon show two major metabolites A-demethylation due to CYP3A4/5 and Ai-deacetylation by carboxylesterases. Its short half-hfe has enabled the development of two dosing paradigms with different formulations (1) an immediate release formulation to improve sleep initiation and for dosing in the middle of the night, and (2) a modified release formulation, which provides for immediate release and sustained release of the drug to help with sleep initiation, duration, maintenance, and sleep quality (Neubauer,... 

Biobatch The lot of drug product formulated for purposes of pharmacokinetic evaluation in a bioavailabUity/bioequivalency study. For modified release solid oral, this batch should be 10% or greater than the proposed commercial production batch or at least 100,000 units, whichever is greater. 

Once-daily administration of modified-release formulation of fluvastatin 80-320 mg/day was generally safe and well tolerated in 40 patients with primary hypercholesterolemia over 13 days (7). However, fluvastatin 640 mg in this formulation was not well tolerated six of seven patients had adverse events, including diarrhea, headache, and rises in serum transaminases. In addition, the pharmacokinetics of fluvastatin were non-linear at this dose, possibly because of saturation of first-pass metabolism, causing higher than expected serum drug concentrations. 

Modified-release formulations of nicotinic acid do not appear to be better tolerated than regular formulations, flushing and itching being the most common adverse effects (SEDA-19, 206). There have also been several reports of hepatotoxicity with this form of the drug (SEDA-16,438). Other adverse effects are hepatotoxicity (apparently a dose-related direct toxic effect), hyperglycemia, and hyperuricemia. It has been questioned whether the modified-release formulation, which is available over the counter in some countries, ought to continue to be available for self-medication in view of its serious adverse effects (2,3). 

R. H. Muller, C. Jacobs, and 0. Kayser. DissoCubes—A novel formulation for poorly soluble and poorly bioavailable drugs, in Michael J. Rathbone, Jonathan Hadgraft, and Machael S. Roberts (eds.), Drugs and the Pharmaceutical Sciences, Vol. 126 Modified-Release Drug Delivery Technology. New York Marcel Dekker, 2003, pp. 139-149. 

An NDA can be submitted for a previously unapproved new molecular entity, or for a new salt, new ester, prodrug, or other noncovalent derivative of a previously approved new molecular entity, formulated as a modihed-release drug product. The first modified-release drug product for a previously approved immediate-release drug product should be submitted as an NDA. Subsequent modified-release products that are pharmaceutically equivalent and bioequivalent to the listed drug product should be submitted as ANDAs. BA requirements for the NDA of an extended-release product are listed in 320.25(f). The purpose of an in vivo BA study for which a controlled-release claim is made is to determine if all of the following conditions are met. 

Immediate release tablets are formulated to release the (API) as soon as possible to hasten absorption. Modified release formulations release the API at a controlled rate. Modified release formulations can be classified into controlled release and extended release formulations. The intention of these formulations is to allow a reduction in dosing frequency or diminish the fluctuation of drug levels on repeated administration compared with that observed with the immediate release form of the drug. 

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